Triple Therapy in RA: The Debate Continues

Jonathan Kay, MD


December 13, 2013

This feature requires the newest version of Flash. You can download it here.

Hello. I'm Jonathan Kay, Professor of Medicine and Director of Clinical Research in the Division of Rheumatology at UMass Memorial Medical Center and the University of Massachusetts Medical School, both in Worcester, Massachusetts. Welcome to my Medscape blog.

At the American College of Rheumatology Annual Meeting in San Diego, there were a number of presentations about triple-therapy treatment with methotrexate, sulfasalazine, and hydroxychloroquine. This was a relatively hot topic this year, beginning with the great debate between Jim O'Dell and Ron van Vollenhoven on the first day of the meeting.[1] In this debate, Jim O'Dell posited that triple therapy is less expensive and as effective as biologic therapy with etanercept. He based his argument on the recent RACAT study,[2] which was published in the New England Journal of Medicine this summer. He also used data from the TEAR study.[3] Both were randomized, placebo-controlled trials of treat-to-target strategies in patients with rheumatoid arthritis.

Ron van Vollenhoven countered the argument by saying that biologic therapy is very effective and certainly has been shown to be more effective than methotrexate monotherapy. He quoted the Swefot trial,[4,5] a trial that was done in Sweden in which patients with early rheumatoid arthritis were treated to target with initial methotrexate therapy. Those who did not achieve low disease activity or remission were randomly assigned to receive either the addition of sulfasalazine and hydroxychloroquine for a triple-therapy treatment strategy or the addition of infliximab for biologic therapy. In that trial, although both groups improved, the group treated with infliximab did a bit better in terms of clinical response. Also, there was less radiographic progression among those treated with infliximab.

Jim O'Dell argued that triple therapy is essentially as effective as initial biologic therapy and certainly more cost-effective. Ron van Vollenhoven countered that certainly one can treat with triple therapy, but the side effects experienced with triple therapy might be less well tolerated than biologic therapy. Of course, how do you argue to a patient that you are going to treat him first with a therapy that might be somewhat less effective than the treatment that you would switch to later on?

There were a number of other triple-therapy abstracts presented at the annual meeting. One was the tREACH study,[6] which looked at the Rotterdam early rheumatoid arthritis cohort. The study compared treatment with triple therapy and intramuscular glucocorticoid bridging therapy vs treatment with triple therapy and oral glucocorticoid bridging therapy vs treatment with initial methotrexate monotherapy and glucocorticoid bridging therapy. As expected, this study showed that the triple-therapy arms were both better than the methotrexate monotherapy arm. In another cost-effectiveness study,both were shown to be more cost-effective overall. A cost-effectiveness analysis of the TEAR study[7] was presented, which showed that the incremental cost of initial etanercept therapy compared with initial triple therapy was $837,000 per quality-adjusted life-year.

There were some other interesting abstracts about triple therapy, several of which dealt with the Swefot study, and they looked at the biomarker disease activity panel. These studies showed that if you use a multibiomarker disease activity panel rather than the C-reactive protein level, you can structurally predict patients who are going to progress and separate them from those who are not. Additionally, looking at individual biomarkers, they found that C-reactive protein, interleukin-6, tumor necrosis factor receptor type 1, and vascular cell adhesion molecule-1 all predicted better clinical outcome. These and several others also predicted better radiographic outcome.

Overall, the excitement about triple therapy raises the question about whether we might not be better off using traditional disease-modifying antirheumatic drugs initially to allow for more patients with rheumatoid arthritis to benefit from therapy than using more expensive therapies initially. This is an ongoing debate for which more data are being generated. More information will appear in the future. I welcome your comments and thank you very much for paying attention to my Medscape blog. I look forward to seeing you again on Medscape.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.